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WO2009091609A1 - Procédé de traitement de syndrome de type diabète induit par la rapamycine à l'aide de la trodusquémine - Google Patents

Procédé de traitement de syndrome de type diabète induit par la rapamycine à l'aide de la trodusquémine Download PDF

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Publication number
WO2009091609A1
WO2009091609A1 PCT/US2009/000341 US2009000341W WO2009091609A1 WO 2009091609 A1 WO2009091609 A1 WO 2009091609A1 US 2009000341 W US2009000341 W US 2009000341W WO 2009091609 A1 WO2009091609 A1 WO 2009091609A1
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WIPO (PCT)
Prior art keywords
trodusquemine
mammal
glucose
pharmaceutically acceptable
dyshomeostasis
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PCT/US2009/000341
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English (en)
Inventor
Michael P. Mclane
Inez Ruiz-White
Henry R. Wolfe
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Genaera Corporation
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Publication of WO2009091609A1 publication Critical patent/WO2009091609A1/fr

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/56—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids
    • A61K31/575—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids substituted in position 17 beta by a chain of three or more carbon atoms, e.g. cholane, cholestane, ergosterol, sitosterol
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
    • A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca

Definitions

  • Trodusquemine (Figure 1) is a non-competitive allosteric inhibitor of protein tyrosine phosphatase IB (PTPlB) that exhibits greater than 150 fold specificity over the highly homologous enzyme, TCPTP.
  • Trodusquemine causes weight loss in wild type, genetically obese, and diet-induced, obese animal models. Phase I clinical trials using trodusquemine for the treatment of obesity were initiated in May 2007. Phase I clinical trials using trodusquemine for the treatment of diabetes were initiated in June 2008.
  • PTP 1 B is known to be a negative regulator of insulin signaling.
  • Trodusquemine is an inhibitor of PTPlB.
  • Insulin is an important regulator of different metabolic processes and plays a key role in the control of blood glucose. Defects related to the synthesis and signaling of insulin lead to diabetes mellitus. Binding of insulin to the insulin receptor (IR) causes rapid autophosphorylation of several tyrosine residues in the intracellular part of the beta-subunit. Three closely positioned tyrosine residues (the tyrosine- 1150 domain) must be phosphorylated to obtain maximum activity of the insulin receptor tyrosine kinase (IRTK), which transmits further signals via tyrosine phosphorylation of other cellular substrates, including insulin receptor substrate-1 (IRS-I).
  • IRTK insulin receptor tyrosine kinase
  • Protein phosphorylation is a well-recognized cellular mechanism for transducing and regulating signals during different stages of cellular function (see, e.g. Hunter, Phil. Trans. R. Soc. Lond. B. 353: 583-605 (1998); Chan et ai. Annu. Rev. Immunol. 12: 555- 592 (1994); Zhang, Curr. Top. Cell. Reg. 35: 21-68 (1997); Matozaki and Kasuga, Cell- Signal. 8: 113-119 (1996)).
  • phosphatases There are at least two major classes of phosphatases: (1) those that dephosphorylate proteins that contain a phosphate group(s) on a serine or threonine moiety (termed Ser/Thr phosphatases or dual specificity phosphatases or DSPs) and (2) those that remove a phosphate group(s) from the amino acid tyrosine (termed protein tyrosine phosphatases or PTPases or PTPs).
  • PTPlB has been identified as at least one of the major phosphatases involved in the IRTK regulation through studies conducted both in vitro (Seely et al. Diabetes 45: 1379-1385 (1996)) and in vivo using PTPlB neutralizing antibodies (Ahmad et al. J. Biol. Chem. 270: 20503-20508 (1995)). Two independent studies have indicated that PTPlB knock-out mice have increased glucose tolerance, increased insulin sensitivity and decreased weight gain on a high fat diet (Elchebly et al. Science 283: 1544-1548 (1999) and Klaman et al. MoI. Cell. Biol. 20: 5479-5489 (2000)).
  • PTPlB tyrosine phosphatase
  • Overexpression or altered activity of tyrosine phosphatase PTPlB can contribute to the progression of various disorders, including insulin resistance and diabetes (Ann. Rev. Biochem. 54: 897-930 (1985)). Furthermore, there is evidence which suggests inhibition of PTPlB is therapeutically beneficial for the treatment of disorders such as type I and II diabetes, obesity, autoimmune disorders, acute and chronic inflammation, osteoporosis and various forms of cancer (Zhang ZY et al. Expert Opin. Investig. Drugs 2: 223-33 (2003); Taylor SD et al. Expert Opin. Investig. Drugs 3:199-214 (2004); J. Natl. Cancer Inst. 86: 372-378 (1994); MoI. Cell. Biol. 14: 6674-6682 (1994); The EMBO J.. 12: 1937-1946 (1993); L Biol. Chem. 269: 30659-30667 (1994); and Biochemical Pharmacology 54:
  • trodusquemine can reverse both short and long term glucose intolerance in a diabetic mouse model and that trodusquemine can reverse hyperglycemia in a diet induced obese animal.
  • trodusquemine is a non-competitive allosteric inhibitor of PTPlB.
  • An aspect of the invention is a method of treating a drug induced diabetic-like syndrome in a mammal, particularly a human, comprising administering to the mammal a therapeutically effective amount of trodusquemine or a pharmaceutically acceptable salt thereof.
  • Another aspect of the invention is a method of decreasing plasma insulin levels in an obese mammal in need thereof, particularly in a human, comprising administering to the mammal a therapeutically effective amount of trodusquemine or a pharmaceutically acceptable salt thereof.
  • Another aspect of the invention is a method of improving fasting blood glucose levels in a mammal in need thereof, particularly in a human, comprising administering to the mammal a therapeutically effective amount of trodusquemine or a pharmaceutically acceptable salt thereof.
  • Another aspect of the invention is a method of preventing an increase in blood glucose levels in a mammal in need thereof, particularly in a human, comprising administering to the mammal a therapeutically effective amount of trodusquemine or a pharmaceutically acceptable salt thereof.
  • Another aspect of the invention is a method of improving glucose tolerance in a mammal in need thereof, particularly in a human, comprising administering to the mammal a therapeutically effective amount of trodusquemine or a pharmaceutically acceptable salt thereof.
  • Another aspect of the invention is a method of treating rapamycin-induced glucose dyshomeostasis in a mammal, particularly in a human, comprising administering to the mammal in need thereof a therapeutically effective amount of a composition comprising trodusquemine or a pharmaceutically acceptable salt thereof.
  • Another aspect of the invention is a method of treating rapamycin-induced hyperglycemia in a mammal, particularly in a human, comprising administering to the mammal in need thereof a therapeutically effective amount of a composition consisting of trodusquemine or a pharmaceutically acceptable salt thereof.
  • Another aspect of the invention is a method of treating rapamycin-induced glucose dyshomeostasis in a mammal, particularly in a human, consisting of administering to the mammal in need thereof a therapeutically effective amount of a composition consisting of trodusquemine or a pharmaceutically acceptable salt thereof.
  • Another aspect of the invention is a method of reversible, non-competitive allosteric inhibition of PTPlB in a mammal in need thereof, particularly in a human, comprising administering to the mammal a therapeutically effective amount of trodusquemine or a pharmaceutically acceptable salt thereof.
  • Another aspect of the invention is a method of treating a disorder in a mammal, particularly in a human, mediated by allosteric inhibition of PTPlB comprising administering to the mammal in need thereof an amount of a composition comprising trodusquemine or a pharmaceutically acceptable salt thereof effective to allosterically inhibit PTPlB.
  • Figure 1 shows the structure of trodusquemine.
  • Figure 2 shows that trodusquemine alleviates rapamycin-induced glucose intolerance.
  • FIG. 3 shows that trodusquemine treatment lowers plasma insulin levels.
  • Figure 4 shows that trodusquemine improves fasting blood glucose.
  • FIG. 5 shows that trodusquemine provides extended improvement of glucose intolerance.
  • FIG. 6 shows that trodusquemine is a reversible inhibitor of PTPlB.
  • Figure 7 shows that trodusquemine is a non-competitive allosteric inhibitor of PTPlB.
  • Trodusquemine (MSI-1436) is an allosteric inhibitor of PTPlB, which has been discovered to elicit weight loss and improve glucose tolerance in a diet-induced model of obesity and genetically obese models. Trodusquemine has also been shown to improve fasting and postprandial blood glucose levels.
  • AKSJJ mice were treated with rapamycin (2 mg/kg daily, IP) to induce an impaired glucose tolerant state.
  • the mice were treated with either MSI-1436 (5 mg/kg, q3dx3, IP) or vehicle and an oral glucose tolerance test (OGTT) was performed 24 days after the last treatment.
  • MSI- 1436 was observed to correct the rapamycin-induced glucose dyshomeostasis.
  • Trodusquemine was also observed to exhibit potent improvement in glucose tolerance in several animal models, which provides additional support for its development as an anti-diabetic therapy.
  • the trosdusquemine may be administered alone or as part of a pharmaceutical composition.
  • Pharmaceutical compositions for use in vitro or in vivo in accordance with the present invention may be formulated in a conventional manner using one or more physiologically acceptable carriers comprising excipients and auxiliaries that facilitate processing of the active compounds into preparations which can be used pharmaceutically. Proper formulation is dependent upon the route of administration chosen.
  • carriers or excipients include, but are not limited to, calcium carbonate, calcium phosphate, various sugars, starches, cellulose derivatives, gelatin and polymers such as polyethylene glycols.
  • compositions of the invention may also optionally include stabilizers, preservatives and/or adjuvants.
  • stabilizers and adjuvants known to those of skill in the art, see Remington: The Science and Practice of Pharmacy. Lippincott, Williams & Wilkins, 21 st ed. (2005), which is incorporated by reference in its entirety.
  • In vivo administration of the trodusquemine can be effected in one dose, multiple doses, continuously or intermittently throughout the course of treatment. Doses range from about 0.01 mg/kg to about 10 mg/kg, such as between about 0.01 mg/kg to about 1 mg/kg, such as between about 0.1 mg/kg to about 1 mg/kg in single or divided daily doses. Methods of determining the most effective means and dosages of administration are well known to those of skill in the art and will vary with the composition used for therapy, the purpose of the therapy, the target cell being treated and the subject being treated. Single or multiple administrations can be carried out with the dose level and pattern being selected by the treating physician.
  • compositions containing trodusquemine can be administered by any suitable route, including oral, rectal, intranasal, topical (including transdermal, aerosol, ocular, buccal and sublingual), parenteral (including subcutaneous, intramuscular, intravenous), intraperitoneal and pulmonary. It will be appreciated that the preferred route will vary with the condition and age of the recipient, and the disease being treated.
  • the trodusquemine can be formulated readily by combining them with pharmaceutically acceptable carriers well known in the art.
  • Such carriers enable the compounds of the invention to be formulated as tablets, pills, dragees, capsules, liquids, gels, syrups, slurries, suspensions and the like, for oral ingestion by a patient to be treated.
  • Pharmaceutical preparations for oral use can be obtained by combining the active compound with a solid excipient, optionally grinding a resulting mixture, and processing the mixture of granules, after adding suitable auxiliaries, if desired, to obtain tablets or dragee cores.
  • Suitable excipients include, for example, fillers such as sugars, including lactose, sucrose, mannitol, or sorbitol; cellulose preparations such as maize starch, wheat starch, rice starch, potato starch, gelatin, gum tragacanth, methyl cellulose, hydroxypropylmethylcellulose, sodium carboxymethylcellulose and polyvinylpyrrolidone (PVP).
  • disintegrating agents may be added, such as the cross-linked polyvinyl pyrrolidone, agar, alginic acid or a salt thereof, such as sodium alginate.
  • the trodusquemine may be conveniently delivered in the form of an aerosol spray presentation from pressurized packs or a nebuliser, with the use of a suitable propellant, e.g., dichlorodifluoromethane, trichlorofluoromethane, dichlorotetrafluoroethane, carbon dioxide or other suitable gas.
  • a suitable propellant e.g., dichlorodifluoromethane, trichlorofluoromethane, dichlorotetrafluoroethane, carbon dioxide or other suitable gas.
  • the dosage unit may be determined by providing a valve to deliver a metered " amount.
  • Capsules and cartridges of e.g., gelatin for use in an inhaler or insufflator may be formulated containing a powder mix of the compound and a suitable powder base such as lactose or starch.
  • the trodusquemine can be formulated for parenteral administration by injection, e.g., bolus injection or continuous infusion.
  • Formulations for injection may be presented in unit dosage form, e.g., in ampoules or in multi-dose containers, with an added preservative.
  • the compositions may take such forms as suspensions, solutions or emulsions in oily or aqueous vehicles, and may contain formulatory agents such as buffers, bacteriostats, suspending agents, stabilizing agents, thickening agents, dispersing agents or mixtures thereof.
  • compositions for parenteral administration include aqueous solutions of the active compounds in water-soluble form.
  • suspensions of trodusquemine may be prepared as appropriate oily injection suspensions.
  • Suitable lipophilic solvents or vehicles include fatty oils such as sesame oil, or synthetic fatty acid esters, such as ethyl oleate or triglycerides or liposomes.
  • Aqueous injection suspensions may contain substances that increase the viscosity of the suspension, such as sodium carboxymethyl cellulose, sorbitol or dextran.
  • the suspension may also contain suitable stabilizers or agents that increase the solubility of the compounds to allow for the preparation of highly concentrated solutions.
  • the trodusquemine is dissolved in a 5% sugar solution, such as dextrose, before being administered parenterally.
  • the trodusquemine may be formulated in aqueous solutions, preferably in physiologically compatible buffers such as Hanks's solution, Ringer's solution or physiological saline buffer.
  • physiologically compatible buffers such as Hanks's solution, Ringer's solution or physiological saline buffer.
  • penetrants appropriate to the barrier to be permeated are used in the formulation. Such penetrants are generally known in the art.
  • Trodusquemine may also be formulated in rectal compositions such as suppositories or retention enemas, e.g., containing conventional suppository bases such as cocoa butter or other glycerides.
  • Trodusquemine may also be combined with at least one additional therapeutic agent.
  • Example 1 Trodnsquemine Reverses Rapamycin Induced Glucose Intolerance.
  • AKR/J mice were treated daily with rapamycin (2 mg/kg; daily from Day -7 to Day 30), trodusquemine (5 mg/kg; Days 0, 3, and 6), or both. After an overnight fast, an oral glucose tolerance was performed (Day 30) by measuring blood glucose levels at 0, 15, 30, 60, 90, and 180 minutes following a p.o. bolus of 1.5 g/kg glucose. Rapamycin was observed to induce an impaired glucose tolerance as compared to saline-treated control mice ( Figure 2). Mice treated with trodusquemine and rapamycin (triangles) demonstrated a significant improvement in glucose intolerance as compared to mice treated with rapamycin alone (circles) as depicted in Figure 2.
  • Example 2 Trodusquemine Reduces Plasma Insulin Levels in Obese Mice.
  • mice Male AKR/J mice were fed ad libitum on a 45% fat kcal or 60% fat kcal diet and postprandial plasma insulin levels were measured after 4 weekly treatments of trodusquemine (10 mg/kg initial dose, 5 mg/kg for subsequent doses). Plasma insulin levels were markedly reduced in trodusquemine-treated mice on both diets. Data is shown in Figure 3.
  • Example 3 Trodusquemine Improves Glucose Tolerance.
  • mice Female ob/ob mice were treated with 5 mg/kg (i.p.) trodusquemine on Days 0, 3, 6, and 9. On Day 21, overnight fasting blood glucose levels were measured (upper right panel as depicted in Figure 4). On Day 30, and following an overnight fast, an oral glucose tolerance test revealed improved glucose tolerance as compared to vehicle control. Data is shown in Figure 4.
  • Example 4 Trodusquemine Provides Extended Improvement of Glucose Tolerance.
  • mice Female ob/ob mice were treated with trodusquemine (5 mg/kg on Days 0, 7, and 14, followed by weekly doses of 1 mg/kg from Days 35-98, and 5 mg/kg on Days 105, 112, and 119) or saline. An OGTT (Day 122) confirmed that improved glucose tolerance is maintained over time. Data is shown in Figure 5.
  • Trodusquemine is a Reversible Inhibitor of PTPlB.
  • PTPlB amino acids 1-436
  • activity was measured in the presence or absence of trodusquemine or suramin (a reversible, competitive PTPlB inhibitor that was used as a positive control) at various time points.
  • Activity was measured as the formation of p- nitrophenyl (pNP) from p-nitrophenyl phosphate (pNPP) substrate at 30 0 C for the indicated time and then quenched with 3N NaOH.
  • Absorbance was read at 405 tun.
  • PTPlB activity was linear over the time period, indicating reversible inhibition. Data is shown in Figure 6.
  • Example 6 Trodusquemine is a Non-Competitive Allosteric Inhibitor of PTPlB.
  • PTPlB activity was measured as the formation of pNP in the presence or absence of trodusquemine with increasing concentrations of pNPP (0.1-100 mM). Activity was measured for 15 min at 30 0 C and then quenched with 3N NaOH. Absorbance was read at 405nm. The inhibition of full-length PTPlB best fits a classic noncompetitive/allosteric model of enzyme inhibition, as shown by a statistically significant decrease in Vmax (p ⁇ 0.01) with no significant change in Km. Data is shown in Figure 7.

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Abstract

L'invention porte sur l'utilisation du trodusquémine pour traiter un syndrome de type diabète induit par la rapamycine chez un mammifère. Les données présentées démontrent que la trodusquémine peut inverser l'intolérance au glucose à court et à long terme, et peut également inverser l'hyperglycémie chez un animal soufftant d'obésité due au régime alimentaire.
PCT/US2009/000341 2008-01-18 2009-01-21 Procédé de traitement de syndrome de type diabète induit par la rapamycine à l'aide de la trodusquémine WO2009091609A1 (fr)

Applications Claiming Priority (4)

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US655008P 2008-01-18 2008-01-18
US61/006,550 2008-01-18
US12969708P 2008-07-14 2008-07-14
US61/129,697 2008-07-14

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Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP2934543A4 (fr) * 2012-12-20 2016-06-22 Mount Desert Island Biolog Lab Stimulation et augmentation de la régénération de tissus

Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2003073987A2 (fr) * 2002-03-01 2003-09-12 Sunesis Pharmaceuticals, Inc. Composes modulant l'activite de ptp-1b et de tc-ptp

Patent Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2003073987A2 (fr) * 2002-03-01 2003-09-12 Sunesis Pharmaceuticals, Inc. Composes modulant l'activite de ptp-1b et de tc-ptp

Non-Patent Citations (2)

* Cited by examiner, † Cited by third party
Title
HUANG ET AL.: "Finding new components of the target of rapamycin (TOR) signaling network through chemical genetics and proteome chips", PNAS, vol. 101, no. 47, 23 November 2004 (2004-11-23), pages 16594 - 16599 *
NEWS RELEASE: "Drugs.com, Genaera Corporation Provides Highlights of Positive Phase 1 Trodusquemine (MSI-1436)", DATA FROM THE NORTH AMERICAN ASSOCIATION FOR THE STUDY OF OBESITY ANNUAL MEETING,, 25 October 2007 (2007-10-25), pages 1 - 4, Retrieved from the Internet <URL:http://www.drugs.com/clinical_trials/genaera-corporation-provides-highlights-positive-phase-1-trodusquemine-msi-1436-data-north-american-2428.html> [retrieved on 20090305] *

Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP2934543A4 (fr) * 2012-12-20 2016-06-22 Mount Desert Island Biolog Lab Stimulation et augmentation de la régénération de tissus
US9504700B2 (en) 2012-12-20 2016-11-29 Mount Desert Island Biological Laboratory Methods and compositions for stimulation and enhancement of regeneration of tissues

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